Members of the alpha virus genus of the Togaviridae family cause significant disease worldwide and are of concern for possible use as bioterrorism weapons. There is no specific therapy for infection with these viruses, which can result in fever, rash, arthritis, encephalitis and death. The objectives of this proposal are to identify host antiviral factors and to identify interactions between host and viral factors that are essential for viral replication. Using Sindbis virus as a model system, 2 approaches will be undertaken. First, libraries of host genes expressed in susceptible cell lines will be screened to identify host factors that can inhibit Sindbis-mediated cell death. The identified genes, or portions of genes, may be functioning directly as an antiviral agent, or in a dominant negative manner to inhibit an essential virus-host interaction. The second approach entails screening a library expressing random fragments of the Sindbis virus genome for those fragments that can act as dominant negative inhibitors of essential virus-host, or virus-virus, interactions. The host genes and viral fragments so identified will provide insight into alphavirus-host interactions. Future studies aimed at understanding the range of viruses affected and the molecular mechanism through which the inhibition occurs might lead to potential targets for the rational design of antiviral therapies for medical and biodefense use. [unreadable] [unreadable]